Numerous studies implicate traumatic brain injury (TBI) as a risk factor for the development of age-related neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, a biochemical link between these disorders is missing. We propose that transglutaminase-2 (TG-2) a member of transglutaminase family could be the possible link between TBI and neurodegenerative diseases. The primary function of TG-2 is to catalyze calcium-dependent cross-linking reactions, which results in protein aggregation. Tau and a-synuclein are the principle components of neurofibrillary tangles (NFTs) and Lewy bodies (LBs), the signature pathological hallmarks of AD and PD respectively. Importantly both tau and a-synuclein are the substrates for TG-2. Recent work in our laboratory showed a sustained induction of TG-2 in the rat brain following traumatic brain injury. Our hypothesis is that TBI-induced TG-2 expression and activation may increase aggregation of tau and a-synuclein proteins and these proteins may become seeds for further homophilic deposition leading to manifestation of AD and PD. Induction of TG-2 protein and mRNA expression and its activity after TBI will be determined after1.6 mm injury magnitude at different time points for 24 months using the control cortical impact rat model. The ability of TG-2 to cross-link tau and a-synuclein proteins will be analyzed by in vitro cross-linking reaction. The antibodies against these cross-linked regions will be developed and used to determine their in vivo colocalization with TG-2 by immunoprecipitation analysis in injured rat brain tissues. In parallel the formation of NFTs and LBs will be determined in aging TBI samples using PHF and LB specific antibodies. We propose to demonstrate that TG-2 is the potential biochemical link between TBI and neurodegenerative diseases by providing evidence of sustained induction of TG-2 and its role in cross-linking of tau and a-synuclein proteins resulting in the formation of PHFs and LBs in aging rats after traumatic brain injury. The proposed study will provide critical information about the prolonged expression and activation pattern of TG-2 following TBI and will lay the necessary foundation for elucidating the potential role of TG-2 as a link between TBI and neurodegenerative diseases. This hypothesis, if proven correct, could lead to the development of potential therapeutic approaches to retard development in aging TBI patient. [unreadable] [unreadable]